Outline

Introduction: Genome-wide association studies have mapped loci that are associated with serum levels of bilirubin. Bilirubin is a major component of gallstones, so we investigated whether these variants predict gallstone bilirubin content and overall risk for gallstones.

Materials and methods: Loci that were identified in a meta-analysis to meet a genome-wide significance level of P<1.0Ã10-7 (UGT1A1, SLCO1B1, LST-3TM12, SLCO1A2) were analyzed in 1018 individuals with known gallstone composition. Gallstone risk was analyzed in 2606 German individuals that received operations for gallstone disease and 1121 controls and replicated in 210 cases and 496 controls from South America.

Results: Using the presence of bilirubin as a phenotype, variants rs6742078 (UGT1A1, P=0.003), rs4149056 (SLCO1B1, P=0.003), and rs4149000 (SLCO1A2, P=0.015) were associated with gallstone composition. In regression analyses, only UGT1A1 and SLCO1B1 were independently retained in the model (r2rs4149056_rs4149000=0.66). UGT1A1 (rs6742078, P=0.018) was associated with overall gallstone risk. In a sex-stratified, post-hoc analysis, only male carriers of rs6742078 had an increased risk for gallstone disease (P=2.1Ã10-7; ORrecessive=2.34; Pwomen=0.47). The sex-specific association of rs6742078 was confirmed in samples from South America (Pmen=0.046; ORrec=2.19, Pwomen=0.96).

Conclusion: The UGT1A1 Gilbert syndrome variant rs6742078 is associated with gallstone disease in men; further studies are required into the sex-specific physiology of bilirubin and bile acid metabolism. Most gallstones associated with UGT1A1 variants are cholesterol gallstones, indicating the role of pigment particles in the pathogenesis of gallstone disease – possibly as nucleation factors. Variants of ABCG8 and UGT1A1 are the 2 major risk factors for overall gallstone disease – they contribute a population attributable fraction of 21.2% among men.